Reimbursement of trial participants remains a frequently debated issue, with specific guidance lacking. Trials combining post-trial access and implementation science may necessitate new strategies and models. CAPRISA 008, a post-trial access study testing the feasibility of using family planning services to rollout a prelicensure HIV prevention intervention, tried to balance the real-life scenario of no reimbursement for attendance at public sector clinics with that of a trial including some visits that focused on research procedures and others that focused on standard of care procedures. A reduced reimbursement was offered for ‘standard of care’ visits, meant primarily to cover transport costs to and from the clinic only. This impacted negatively on accrual, retention and participant morale, primarily due to the protracted delay in regulatory approval, during which time, the costs of living, including travel costs had increased. Relevant guidelines were reviewed and institutional policy was updated to incorporate the South African National Health Research Ethics Committee guidelines on reimbursement (taking into account participant time, travel and inconvenience). The reimbursement amount for ‘standard of care’ visits was increased accordingly. The question remains whether a trial that combines post-trial access with implementation science, with clear benefits for the participants and the provision of above standard medical care, should have reimbursement rates that approach those of a proof-of-concept trial, for ‘standard of care’ visits.
- Research Ethics
- HIV Infection and AIDS
- Interests of Health Personnel/Institutions
- Scientific Research
- Clinical trials
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- Research Ethics
- HIV Infection and AIDS
- Interests of Health Personnel/Institutions
- Scientific Research
- Clinical trials
Reimbursement of trial participants remains a frequently debated issue within research clinical trials nationally and internationally, across both high-income and low/middle-income countries.1–6 Translating the results of phase II/III clinical trials that demonstrate efficacy into practice requires ongoing rigorous implementation science studies, which if combined with post-trial access may necessitate new study participant reimbursement strategies and models. Implementation science trials (phase IIIb), involving study products that are not yet licensed, are uncommon in South Africa, and the conduct of the CAPRISA 008 trial highlighted challenges both in reimbursement and in regulatory approval.
CAPRISA 008 is an open-label randomised controlled trial to assess the implementation, effectiveness and safety of 1% tenofovir gel provision through family planning services in KwaZulu-Natal, South Africa, through combining post-trial access with implementation science. The CAPRISA 004 trial demonstrated 39% reduction in HIV infection, with 54% reduction in women who used tenofovir gel consistently.7 A confirmatory study, FACTS 001, is expected to report results in early 2015, and if it confirms the CAPRISA 004 trial findings, it may provide the information needed to support licensure of tenofovir gel for HIV prevention. Hence, the next 2–3 years are a critical window of opportunity to prepare for and devise effective strategies for the future policy and programmatic scale-up of tenofovir gel provision.
CAPRISA 008 has three main goals: to provide post-trial access to tenofovir gel for HIV-uninfected CAPRISA 004 study participants and surrounding communities, to develop and assess an implementation model for tenofovir gel provision through family planning services and to collect additional safety data on tenofovir gel. The study will include up to 700 consenting sexually active, HIV-uninfected South African women aged ≥18 years who previously participated in the CAPRISA 004 study. UNAIDS Guidance point 19 recommends that researchers provide post-trial access of efficacious products to former participants and to other populations at higher risk of HIV exposure in the country. The South African Medicines Control Council (MCC) approved only inclusion of former participants of CAPRISA 004 for enrolment, which resulted in a cohort of research-experienced participants in CAPRISA 008. This open-label study is being conducted at the CAPRISA Vulindlela and eThekwini Clinical Research sites in KwaZulu Natal, South Africa (the same clinics used in the CAPRISA 004 trial), and their neighbouring family planning clinics. Participants will be randomised to receive tenofovir gel either through the public sector family planning services with 2–3 monthly provision and monitoring of the gel, together with quality improvement to promote reliable service delivery (intervention arm), or through the CAPRISA research clinics with monthly provision and monitoring of tenofovir gel (control arm). All women in the trial will be provided with the standard package of HIV prevention and reproductive health services.
The recent practice of researchers in South Africa is to adopt or adapt the MCC's previously recommended flat rate of rands 150-00i for reimbursement in clinical trials. As very little specific guidance exists for investigators,2 this often results in varying reimbursements for participants in similar trials across collaborating sites and within a site conducting multiple trials, and creates controversy and dissatisfaction among participants and researchers.
Joint United Nations Programme on HIV/Acquired Immune Deficiency Syndrome (UNAIDS) International guidelines recommend that reimbursement for travel, other expenses or incentives related to study participation (acknowledging time and inconvenience) be determined by the local economic and social contexts.8 South African guidelines endorse reasonable and fair reimbursement, including incentives to participate.9 In practice, the MCC's flat rate for clinical trials is administered such that all participants receive the same reimbursement, irrespective of time, travel and inconvenience.1 In 2012, the National Health Research Ethics Committee (NHREC) in South Africa released a guideline for ethics committees on considerations for reimbursement of trial participants, detailing that the MCC flat rate may have been misunderstood and applied incorrectly by stakeholders.6 The NHREC guideline recommendation is that the amount and schedule of participant reimbursement, in consultation with the community, should consider participant time commensurate with unskilled labour rates, inconvenience or discomfort due to study procedures and direct costs (travel, meals and childcare).6 This implies that for shorter study visits with less invasive procedures and discomfort to the participant, a lower reimbursement should be considered.
Type of reimbursement
Different types of reimbursement have been recognised: ‘Compensation payment’ for time, inconvenience and other research burdens (not including risk); ‘Re-imbursement payment’, which refunds participants for direct costs; ‘Incentive payment’, which exceeds compensation and encourages enrolment and ‘Appreciation Payment’, which is additional payments in gratitude for participant's effort usually administered at study end.10
Timeline for regulatory approval
There was a considerable time lapse between the initial protocol submission to the MCC on 18 November 2010 and the final approval on 21 May 2012 (table 1). In this time, the Consumer Price Index, which measures changes in the prices paid by consumers for a basket of basic goods and services, and is a proxy for the cost of living, rose from approximately 89 index points in November 2010 to 97 index points by May 2012.11
Reimbursement challenges in CAPRISA 008
The reimbursement schedule in CAPRISA 008 for ‘standard of care’ visits was approximated to that of a woman's attendance at her local clinic, where services are rendered free and without reimbursement for transport, time and inconvenience for the visit. A minimum reimbursement to cover transport for these visits was scheduled because the study protocol required participants to attend designated clinics and not the clinic closest to their place of residence or work. These visits are similar to standard of care sexual reproductive healthcare visits conducted at primary care clinics, and require no research procedures. Participants were compensated rands 50-00 for the screening visit and an additional rands 50-00 for the enrolment visit. Thereafter, they were compensated rands 20-00 for each shorter ‘standard of care’ scheduled study visit. In addition, every 6 months, participants were compensated rands 150-00 for the longer scheduled visit, which included blood draws and collection of genital samples (research visits). For study team-initiated interim visits, participants were compensated rands 20-00. The reimbursement schedule was standardised in both arms of the trial to ensure fairness across study arms. This reimbursement schedule was supported by the Community Research Support Group (CRSG) and approved by the ethics committee.
During the early screening and enrolment visits, participants began sharing their concerns (either verbally or via the suggestion box) with regard to the reimbursement amounts. These included:
Travel costs to the research site/designated neighbouring family planning clinic required subsidisation by the majority of participants.
The length of study visits and required study procedures were not proportionate to the reimbursement.
The reimbursement did not compensate for direct expenses, for example, paying for childcare during visits, loss of formal and informal income on the day of the visit.
Although CAPRISA 008 provided post-trial access to tenofovir gel (a personal benefit to participants), it still had scientific and community interests (providing evidence for accessibility of product), and participants advocated that they were still participating in a clinical trial.
Participants associated the value of their participation with the reimbursement amount and the decrease in amount from the proof-of-concept efficacy trial (CAPRISA 004)7 to that of the post-trial access trial/implementation science trial, made them feel devalued.
Impact on accrual and retention
Enrolment began on 7 November 2012, with screening:enrolment ratios for November 2012 at 1.47:1.00 for the rural and 4.33:1.00 for the urban site. By 31 January 2013, 62% of the 113 urban and 72% of 215 rural volunteers contacted telephonically had presented for screening. Participants ascribed their unwillingness to participate to the low reimbursement, with several participants indicating that they could not afford to attend for screening until the reimbursement had been increased. The overall retention rate for December 2012 was 62% and 66% for January 2013, below the protocol standard of 90% per month (figure 1). Retention in the urban site dropped from December to February and then recovered once the Biomedical Research Ethics Committee (BREC) approval for the improved reimbursement was implemented (figure 1). The effect was less marked in the rural site, where retention increased slowly during December 2012 to February 2013, with a sharper increase in retention once the new reimbursement rates were implemented (figure 1).
In order to understand the extent of the problem, the study team undertook a review and analysis of participant return travel costs based on public transport fares between December 2012 and February 2013. While this review was in process, the team offered the following to all participants:
transport to the clinic for groups of participants at allocated pick-up points;
additional refreshments based on the length of the visits, including refreshments for participants’ children who accompanied them to the visits;
early morning/late afternoon and Saturday clinic visits for employed participants;
streamlined visit flows to reduce the time spent waiting in the clinic.
Numerous meetings were held with the senior protocol team, site study teams, the CRSGs and participants to discuss concerns regarding the reimbursement rates, anticipated effects on accrual and retention, as well as suggested solutions. In addition, face-to-face meetings were held between coinvestigators and participants to acknowledge concerns, find an acceptable compromise and to propose a way forward. The CAPRISA's bioethics head was tasked with drafting a CAPRISA policy regarding participant reimbursements in clinical trials, to reflect reimbursement for time, inconvenience and expenses for visits as indicated in the latest guidelines introduced by the NHREC.6 ,7 The draft proposal recommended that all participants should receive rands 50-00 for transport. Thereafter, participants should be reimbursed for time and inconvenience according to two categories , that is, <4 h and >4 h spent in clinic—calculated at rands 12-50 per hour, which is based on the minimum unskilled approved wage. So, if a study visit is anticipated to be <4 h long, a participant will receive rands 50-00 and if >4 h long, a participant will receive rands 100-00. Based on this proposal, the reimbursement rates for the CAPRISA 008 study were adjusted and approved by the UKZN BREC as indicated in table 2.
The study enrolment informed consent document was amended to incorporate the reimbursement adjustments, and a submission was made to the UKZN BREC for approval. This submission included letters of support from the CRSG. The revised informed consent document was approved by the UKZN BREC, and the adjusted reimbursement implemented on 9 March 2013.
The CAPRISA 008 V.2.0 protocol with the informed consent forms (ICFs) reflecting the original reimbursement schedule was approved by the University of Kwazulu Natal’s Biomedical Research Ethics Committee on 3 October 2012. Zulu and English enrolment ICFs, which reflected the updated reimbursement schedule, were approved on 1 March 2013, and approval was ratified on 12 April 2013.
Reimbursement for trial participation remains controversial, with limited guidance for investigators in South Africa and developed countries in recent years.2 ,12 Investigator's opinion may be influenced by anecdotal experiences with some trial participants, where the primary interest in participation is driven by financial gain, and may constitute an undue inducement for indigent participants. A South African trial (n=250) documenting participant opinion on reimbursements in clinical trials sought to clarify the amount of money that would constitute an undue inducement.2 Although 66.5% were unemployed and 64.0% were dependent on the state alone for healthcare, 93.6% indicated that they would still participate in a clinical trial if they received no reimbursement.2 However, 74.0% felt that participants should receive reimbursement, mostly to cover travel expenses, with only 6.4% reporting use of reimbursement for necessities.2 The CAPRISA 008 participants mostly reported interest in gaining post-trial access to the gel to reduce HIV risk, but were challenged to do so given the cost of transport, the duration of ‘standard of care’ visits, uncompensated time off work and lack of recognition for contribution to science.
A review of seven studies in developed countries found that financial remuneration was a significant motivator for volunteering among normal healthy volunteers.4 The assumption was that the benefits to normal healthy volunteers in a clinical trial are limited, and thus, could not influence the decision to participate.4 CAPRISA 008 is a post-trial access implementation trial, using an unlicensed product where the phase IIb proof-of-concept trial has shown safety and 39.0% efficacy7; participants are healthy women at high risk of HIV acquisition who will benefit personally from post-trial access to an effective product; the thinking of the protocol team when the protocol was first submitted for regulatory review was that for ‘standard of care’ visits, reimbursement to cover the cost of travel to and from the research clinics only was sufficient. In fact, the primary motivator in CAPRISA 008 participants remains access to study product, with financial remuneration expected to cover personal travel costs, time and inconvenience, as well as recognition for their participation in a trial.
The recommendation when deciding whether to offer reimbursement is that investigators should take into account the nature of the study, the nature of participant contributions and vulnerabilities, institutional or organisational guidelines and local societal and cultural norms.1 CAPRISA 008 initially took into account the study design, assigning a lower reimbursement for ‘standard of care’ visits, given the superior staffing to client ratios and the provision of above standard of care service in research versus public sector clinics. Standard of care service provision in the trial exceeds that in the public sector, in that Papanicolaou (Pap) smears are offered to all participants irrespective of age, updated research findings on available contraception is communicated to participants and an expanded method mix is strongly promoted, and all sexual reproductive services, including HIV testing and counselling and management of minor ailments are provided by the same healthcare provider in one visit. Thus, the time spent in the clinic and the inconvenience of the procedures done at these visits do not exceed what is normally experienced in a public sector clinic. However, the research team did not factor in the additional time spent travelling to and from the designated clinics or the impact that the protracted approval process and resultant changes in inflation and the costs of living had on transport costs, prior to study initiation. Thus, a reimbursement rate appropriate to a visit 2 years previously was implemented 2 years later, without adjustment. Prior to this event, CAPRISA, like many other research organisations in South Africa, implemented the MCC-recommended flat-rate reimbursement of rands 150 per visit. The resultant participant dissatisfaction and negative impact on early recruitment and retention culminated in the review of this standard, the adaptation of the NHREC guideline and the development of an institution-wide draft policy for participant reimbursement for all trials, based on time, inconvenience and expenses, using the national unskilled labour remuneration rates to calculate the amount to be paid for time spent for a visit, including the travel time to and from the clinic.
The restricted approval granted by the MCC limited participation to a research-experienced cohort, some of whom expected reimbursement levels similar to that of the efficacy trial from which they were drawn. Furthermore, participants had become accustomed to the rands 150 flat rate, and were less knowledgeable that reimbursement should cover direct costs, time, travel and inconvenience. Some participants felt that the reimbursement amount was reflective of the researchers appreciation of their participation, hence, the demoralisation when the reimbursement rate was reduced. The restricted approval made the study findings less generalisable, but also made an assessment of interest in the gel, outside of a trial with reimbursement, more challenging. Unlicensed tenofovir gel can only be distributed in South Africa within the confines of a clinical trial, the logistical and budgetary restrictions of which made implementation at local clinics less likely. Most participants had to travel to reach the designated public sector and research clinics, which increased costs and limited the approximation of real-world settings.
Limited empirical work has been conducted on participant reimbursements in general in South Africa, with no work on reimbursement specific to combined postaccess and implementation science trials. This results in the lack of systematic data collection using standardised validated tools. Instead, study decisions on reimbursement are informed by a collection of experiences of site staff, subjective interpretation of existing guidelines, reports from various meetings and community and participant input as the issue unfolded, which could be subject to bias. The swift reaction by CAPRISA staff on every level was a definite strength in strategically addressing participant concerns. A review of the wider literature examining reimbursement regulations and guidelines in the USA, Japan, Europe and Australia reveals that these documents advise the ethics committees to assess whether payment is an undue inducement or not, but have very little detailed guidance on how much or when payment should be made.13–15 Furthermore, in an analysis of current US policies, only 37.5% of organisations reported having written policies or guidelines on reimbursement, which was mostly done based on time (87%), inconvenience (84%) and less so on travel (68%).16
Combining a postaccess trial with an implementation trial was informed by the obligation that researchers have to provide post-trial access to proven effective products and the dire need to inform efficient programmatic roll out of a proven HIV prevention technology in a high-risk endemic setting, where options for HIV prevention that are women initiated and controlled are limited. The protracted regulatory review, punctuated by requests for face-to-face meetings with investigators and a regulator-hosted scientific review of the technology, is indicative of the novelty of this approach even for the regulator, especially against the background of recent unsuccessful microbicide trials.17 ,18 The researchers in an effort to ensure timely post-trial access did not factor in the change in transport costs during this delay.
A positive finding emanating from the reimbursement issue within CAPRISA 008 was the quality and timeliness of the engagement between study staff and the participants after participant complaints and the impact on retention, which demonstrates the importance CAPRISA places on the continued collaboration between research staff and participants in the conduct of study protocols. While this swift reaction by staff on every level was a definite strength in strategically addressing participant concerns, it remains clear that many of these concerns could have been pre-empted if the rise in the inflation rate and cost of living had been factored into the reimbursement prior to study initiation, given the delays in regulatory approval.
Changes in reimbursement schedules when moving from an efficacy to a combined post-trial access and implementation science trial, without sufficient consideration of the effect that delays in regulatory approvals and the resulting increase in the cost of living and changes to the study population have on reimbursement amounts, can have negative impacts on accrual and retention, with a potential to reduce sample size and impair the validity of the findings. Researchers should be cognisant of the changes in the cost of living during these delays and reconsult with community representatives and ethics committees to assess the adequacy of reimbursement levels prior to study initiation. The time spent achieving this should be balanced with the obligation to provide post-trial access without unnecessary delays. Given the dearth of specific empirical information guiding investigators on participant reimbursement in South Africa, critical review of existing guidelines and sharing of challenges and solutions will alert stakeholders to the complexities of reimbursement strategies during protocol design and regulatory delays. Communities need to be educated on what informs reimbursement amounts to bridge the gap between expectations and reality. The question remains whether a trial that combines post-trial access with implementation science, with clear benefits for the participants and the provision of above standard medical care, should have reimbursement rates that approach those of a proof-of-concept trial, for ‘standard of care’ visits.
Contributors KTM is the primary and corresponding author, wrote the first draft of the manuscript and was responsible for submission and all revisions. JF (1), CM (1), JS (1, 2), NN (1), NM (1), FN (1), LL (1), QAK (1, 3) and LM (1) are all coauthors who reviewed and provided input to the first draft and reviewed and approved any revisions. LM is the coinvestigator and the overall study coordinator and QAK is the principal investigator; both provided the same input to the first draft and revisions as the other authors.
Competing interests None declared.
Ethics approval University of Kwazulu Natal Biomedical Research Ethics Committee.
Provenance and peer review Not commissioned; internally peer reviewed.
Data sharing statement The primary manuscript for this protocol has not been published; data clean-up is still in progress. All data are available to the investigators primarily and to the coauthors on request to the investigators.
↵i Equivalent of US$15.79 at current exchange rate, rand 1=US$9.95.
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